PROJECT SUMMARY/ABSTRACT This K01 Career Development Award will support the training and career development of a junior investigator, Dr. Sarinnapha Vasunilashorn, in patient-oriented aging research. The overall goal of the proposal is to provide Dr. Vasunilashorn with critical skills and development of experience and competence as an independent, translational researcher in delirium and Alzheimer's Disease and Related Dementias (ADRD). Specific training goals include: 1) obtaining experience in primary data collection within a clinical setting, 2) expansion of her analytic skillset in advanced longitudinal methods and genetic data analysis, and 3) building an in-depth knowledge base of ADRD. These training goals will be conducted in coordination with a set of specific research projects based on Dr. Vasunilashorn's preliminary data that reports on the association between plasma inflammatory markers and the incidence and severity of postoperative delirium in older patients without ADRD undergoing non-cardiac surgery. Delirium and ADRD have strong epidemiological associations: ADRD has long-been recognized as a risk factor for delirium, and recently delirium has been implicated as a risk factor for incident ADRD. Although this points to a clear link between delirium and ADRD, the shared pathophysiology underlying these relationships remains largely unknown. In the proposed K01 Specific Aims, Dr. Vasunilashorn will address this gap in knowledge and substantially extend her preliminary studies that have focused only on plasma-based markers of inflammation by examining whether both plasma and cerebrospinal fluid (CSF)-based measures of neuroinflammation and neuronal injury are associated with postoperative delirium, long-term cognitive decline, and incident ADRD, and evaluate whether genetic risk modifies these associations. These studies will leverage the considerable resources of: 1) the NIA-funded program project, the Successful Aging after Elective Surgery Study (SAGES; P01AG031720), and 2) the Healthier Postoperative Recovery Study (HiPOR; R21AG048600). This proposal is highly novel in examining markers of neuroinflamamtion and neuronal injury that will advance our understanding of the pathophysiologic mechanisms underlying the delirium-ADRD relationship, a largely underexplored area that represents a top priority area of the NIH (PAR-17-038). Importantly, the results will inform pathophysiologically targeted treatment for inflammation to provide neuroprotection and identify important variables to refine delirium risk prediction strategies thereby potentially preventing delirium and reducing ADRD. Ultimately, this work will pave the way and provide the foundation for the launch of Dr. Vasunilashorn's independent research career that will explore the pathophysiologic linkages of delirium and ADRD, two major threats to the independence and quality of life of all older adults.